Alternating sympathomimetic therapy for the treatment of respiratory aliments

ABSTRACT

A combination of dosage units for alleviating respiratory ailments and a method of alleviating respiratory ailments which uses this combination of dosage units. The dosage units comprise one or more first dosage units comprising pseudoephedrine and/or a pharmaceutically acceptable salt thereof and one or more second dosage units comprising phenylephrine and/or a pharmaceutically acceptable salt thereof. This Abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a combination of dosage units foralleviating/treating respiratory ailments such as nasal congestion andto a method of alleviating/treating respiratory ailments which uses thiscombination of the dosage units. The dosage units comprise one or morefirst dosage units comprising a first sympathomimetic agent, i.e.,pseudoephedrine and/or a pharmaceutically acceptable salt thereof, andone or more second dosage units comprising a second sympathomimeticagent, i.e., phenylephrine and/or a pharmaceutically acceptable saltthereof.

2. Discussion of Background Information

Pseudoephedrine and its pharmaceutically acceptable salts are powerfulsympathomimetic agents used for the control of allergic manifestationsand for decongestion of respiratory airways in human subjects. However,pseudoephedrine containing products often give rise to excessive plasmaconcentrations when ingested according to dosage directions. Theselevels can reach blood concentrations that are 75% to 200% higher thanthe concentration needed for therapeutic effects.

Current dosage schedules of pseudoephedrine containing productsavailable in the United States contain labels that instruct adultpatients to ingest a maximum dosage of 60 mg of immediate releasepseudoephedrine hydrochloride or other pharmaceutically acceptable saltsthereof every 4 to 6 hours, but not to exceed 240 mg in a 24 hourperiod. Sustained release oral dosage forms of pseudoephedrine instructan adult person to ingest 120 mg per dose every 12 hours, or 240 mg perdose in case of a 24 hour dosage form.

Regardless of whether the ingested dosage form is an immediate or acontrolled release dosage form, at the end of the dosage cycle theplasma concentration of pseudoephedrine will still be above or barelybelow the therapeutic level, since the half life of pseudoephedrine isabout 6 to 8 hours. Accordingly, it is inevitable that the second andall subsequent doses will exceed the minimum therapeutic plasmaconcentration by 75% to 200%, depending on whether the dosage is takenevery 4 hours or every 6 hours or is taken in the form of a controlledrelease dosage unit.

There is no question that excessive therapeutic levels ofpseudoephedrine of the order of 75% to 200% will more likely provoke theknown side effects thereof such as, e.g., cardiovascular stimulationwith elevated blood pressure, tachycardia or arrhythmias, centralnervous system stimulation with resulting nervousness, excitability,restlessness, dizziness, weakness, insomnia, anxiety, tremors,hallucinations, skin rashes, urinary retention, headache and drowsiness.Large doses of pseudoephedrine may also cause lightheadedness, nauseaand/or vomiting. Pseudoephedrine may further increase the irritabilityof the heart muscle and may alter the rhythmic function of theventricles, especially in large doses or when administered to patientswho are hypersensitive to the myocardial effects of sympathomimeticdrugs.

A way to prevent excessive plasma concentrations of pseudoephedrinewould be to allow the blood levels of pseudoephedrine to fall low enoughso that the second and subsequent dosages do not add excessive amountsof the agent into the blood stream. However, this solution appearscontrary to both precedent and conventional medical practice, since itwould leave the patient suffering from respiratory ailments relating toallergies, common colds, or other common types of respiratory ailmentsfor which sympathomimetics are indicated without adequate medication forseveral hours each day.

In view of the foregoing, there is a need to avoid excessive plasmaconcentrations of pseudoephedrine during the continued administration ofpseudoephedrine dosage forms without interrupting the therapeutic effectprovided by pseudoephedrine.

SUMMARY OF THE INVENTION

The present invention provides a combination of oral dosage units foralleviating respiratory ailments such as nasal congestion. Thecombination comprises one or more first dosage units which comprisepseudoephedrine and/or a pharmaceutically acceptable salt thereof andone or more second dosage units which comprise phenylephrine and/or apharmaceutically acceptable salt thereof. At least one of the first andsecond dosage units comprises an antihistamine and/or is free of anexpectorant and/or is free of a cough suppressant.

In one aspect of the combination, the first and/or the second dosageunits may comprise at least one additional active ingredient such as,e.g., an antihistamine and/or a cough suppressant, and/or anexpectorant, and/or an analgesic and/or an anti-inflammatory agent. Forexample, one or both of the first and second dosage units may compriseone or more antihistamines and/or one or both of the first and seconddosage units may comprise one or more cough suppressants.

In another aspect of the combination, the first and second dosage unitsmay each independently comprise an antihistamine and/or a coughsuppressant and/or an expectorant and/or an analgesic and/or ananti-inflammatory agent. By way of non-limiting example, both the firstand second dosage units may comprise an antihistamine and/or a coughsuppressant, or one of the first and second dosage units may comprise anantihistamine and the other one of the first and second dosage units maycomprise a cough suppressant. Particularly, at least the first dosageunit may comprise one or more antihistamines and at least the seconddosage unit may comprise one or more cough suppressants.

In yet another aspect of the combination of the present invention, thefirst dosage units may further comprise one or more additional activeingredients which are selected from chlorpheniramine, promethazine,carbetapentane, codeine and pharmaceutically acceptable salts thereofand/or the second dosage units may further comprise one or moreadditional active ingredients which are selected from chlorpheniramine,dexchlorpheniramine, carbinoxamine, hydrocodone, codeine, guaifenesinand pharmaceutically acceptable salts thereof.

In a still further aspect of the combination of the present invention, asingle first dosage unit may comprise from about 90 mg to about 150 mgof pseudoephedrine hydrochloride or an equivalent amount (in terms ofmoles of base compound) of pseudoephedrine and/or anotherpharmaceutically acceptable salt thereof and/or a single second dosageunit may comprise from about 20 mg to about 40 mg of phenylephrinehydrochloride or an equivalent amount (in terms of moles of basecompound) of phenylephrine and/or another pharmaceutically acceptablesalt thereof. For example, a single first dosage unit may comprise fromabout 100 mg to about 140 mg of pseudoephedrine hydrochloride or anequivalent amount of pseudoephedrine and/or another pharmaceuticallyacceptable salt thereof, and a single second dosage unit may comprisefrom about 25 mg to about 35 mg of phenylephrine or an equivalent amountof phenylephrine and/or another pharmaceutically acceptable saltthereof.

In another aspect of the combination, the first and second dosage unitsmay independently comprise tablets, capsules, powders, solutions,suspensions, gels and syrups. For example, the first and second dosageunits may both comprise suspensions or the first and second dosage unitsmay both comprise tablets such as, e.g., multilayered (for example,bi-layered) tablets.

In another aspect of the combination, the first and/or the second dosageunits may comprise a controlled release formulation and/or the firstand/or the second dosage units may comprise an immediate releaseformulation.

In yet another aspect of the combination, the first and/or the seconddosage units may comprise multilayered tablets. For example, the firstand second dosage units may both comprise multilayered tablets, e.g.,bi-layered tablets. For example, a multilayered tablet of the firstdosage unit may comprise a first layer which is an immediate releaselayer and a second layer which is a controlled release layer and/or amultilayered tablet of the second dosage unit may comprise a first layerwhich is an immediate release layer and a second layer which is acontrolled release layer.

In another aspect, the first (immediate release) layer of a multilayeredtablet of the first dosage unit may comprise an antihistamine and/or amultilayered (e.g., bi-layered or tri-layered) tablet of the seconddosage unit may comprise two different controlled release layers. Forexample, at least one of the two controlled release layers may comprisea cough suppressant.

In another aspect of the present invention, the combination may be apackaged combination which may comprise the first dosage units containedin at least one first container and the second dosage units contained inat least one second container.

In yet another aspect of the present invention, the combination mayfurther comprise instructions directing ingestion of the first dosageunits prior to periods during which a subject intends to be awake (alsoreferred to herein as “daytime administration”) and ingestion of thesecond dosage units prior to periods during which a subject intends tosleep (also referred to herein as “nighttime administration”).

The present invention further provides a regimen for the alleviation ofrespiratory ailments such as nasal congestion. The regimen comprises theadministration to a subject in need thereof of one or more first dosageunits which comprise pseudoephedrine and/or a pharmaceuticallyacceptable salt thereof in an amount which is sufficient to maintain atherapeutically effective plasma level of pseudoephedrine for a firstperiod, and subsequently the administration to the subject of one ormore second dosage units which comprise phenylephrine and/or apharmaceutically acceptable salt thereof in an amount which issufficient to maintain a therapeutically effective plasma level ofphenylephrine for a second period. The first and second dosage units areadministered such that there is substantially no time gap between thefirst and second periods.

In one aspect of the regimen, there may be substantially no overlapbetween the first and second periods.

In another aspect of the regimen, the first and the second periodstogether may be about 24 hours long and/or the first period may be fromabout 12 hours to about 16 hours long.

In yet another aspect of the regimen, a one-time administration of theone or more first dosage units may be sufficient to maintain atherapeutically effective plasma level of pseudoephedrine over theentire first period and/or a one-time administration of the one or moresecond dosage units may be sufficient to maintain a therapeuticallyeffective plasma level of phenylephrine over the entire second period.

In a still further aspect of the regimen, the first period maysubstantially coincide with the period during which the subject intendsto be awake, and the second period may substantially coincide with aperiod during which the subject intends to be asleep.

In yet another aspect, the administration of the first dosage unit andthe subsequent administration of the second dosage unit may be repeatedat least once.

In another aspect of the regimen, the minimum therapeutically effectiveplasma level of pseudoephedrine may not substantially be exceeded overthe entire first period.

In yet another aspect of the regimen of the present invention, the firstand/or the second dosage units may further comprise at least oneadditional active ingredient such as, e.g., an antihistamine and/or acough suppressant and/or an expectorant and/or an analgesic and/or ananti-inflammatory agent.

In another aspect of the regimen, the period of the therapeutic plasmalevel of the at least one additional active ingredient may overlap withat least about 70% of the first period or the second period,respectively.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The particulars shown herein are by way of example and for purposes ofillustrative discussion of the embodiments of the present invention onlyand are presented in the cause of providing what is believed to be themost useful and readily understood description of the principles andconceptual aspects of the present invention. In this regard, no attemptis made to show details of the present invention in more detail than isnecessary for the fundamental understanding of the present invention,the description making apparent to those skilled in the art how theseveral forms of the present invention may be embodied in practice.

The present invention provides a combination which comprises one or morefirst dosage units comprising pseudoephedrine and/or a pharmaceuticallyacceptable salt thereof and one or more second dosage units comprisingphenylephrine and/or a pharmaceutically acceptable salt thereof.

The combination of the present invention generally minimizes or at leastsubstantially reduces the side effects associated with theadministration of pseudoephedrine by avoiding overdosing ofpseudoephedrine caused by second and subsequent intakes. The presentinvention addresses the problem of overdosing pseudoephedrine byadministering pseudoephedrine and phenylephrine in substantiallyalternating order, which allows the pseudoephedrine plasma concentrationto fall low enough so that the subsequent administration ofpseudoephedrine does not cause an excessive plasma concentration ofpseudoephedrine, i.e., a concentration which is significantly higherthan the minimum therapeutically effective plasma concentration, and atthe same time allows to maintain the needed therapeutic relief byproviding the sympathomimetic agent phenylephrine.

Phenylephrine is a powerful sympathomimetic agent recognized by theFederal Food and Drug Administration as effective for the treatment ofthe same medical indications as pseudoephedrine (it is related to themost effective anti-allergic sympathomimetic agentavailable—epinephrine—known by its trade name ‘adrenalin’—whereaspseudoephedrine is related to ephedrine). Phenylephrine actually slowsthe heart rate, when given in adequate dosages. This action isdiametrically opposed to the increase in heart rate associated withadverse effects of pseudoephedrine. Phenylephrine also has a muchshorter therapeutic half-life than pseudoephedrine—only about 2½hours—so the elimination of this agent from the blood stream occurs muchmore rapidly after the levels fall below therapeutic levels and for thisreason an excessive build-up of this sympathomimetic agent in the bloodstream is prevented when the alternate pseudoephedrine dosage isingested.

The first and second dosage units of the combination of the presentinvention may comprise additional active ingredients such as, e.g.,antihistamines, cough suppressants, expectorants, analgesics andanti-inflammatory agents. The additional active ingredients may bepresent independently in both the first and second dosage units or inonly one of these dosage units. For example, the first dosage units maycomprise one or more additional active ingredients and the second dosageunits may comprise one or more additional active ingredients. The one ormore additional active ingredients in the first dosage units may be thesame as or different from the one or more additional active ingredientsin the second dosage units. Also, the additional active ingredients inthe first and second dosage units may partially overlap. By way ofnon-limiting example, the first dosage units may comprise a firstadditional active ingredient and a second additional active ingredientand the second dosage units may comprise a first additional activeingredient and a second additional active ingredient. In this case thefirst and second additional active ingredients of the first dosage unitsand the first and second additional active ingredients of the seconddosage units may be the same or different. Alternatively, the firstadditional active ingredients of the first and second dosage units maybe the same and the second additional ingredients of the first andsecond dosage forms may be different from each other. Of course, theseare but a few examples of combinations of active ingredients that may bepresent in the first and second dosage units.

The antihistamines, expectorants, cough suppressants, analgesics andanti-inflammatory agents which may be comprised in the combination ofthe present invention may be selected from a wide variety of activeingredients. For example, non-limiting examples of suitableantihistamines include astemizole, azatadine, azelastine,bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine,chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine,cyproheptadine, desloratadine, dexbrompheniramine, dimethindene,diphenhydramine, diphenylpyraline, doxylamine, fexofenadine,hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast,phenindamine, pheniramine, phenyltoloxamine, promethazine,prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine,trimeprazine, tripelennamine, triprolidine and pharmaceuticallyacceptable salts thereof such as, e.g., zatadine maleate,bromodiphenhydramine HCl, brompheniramine maleate, carbinoxaminemaleate, cetirizine HCl, chlorcyclizine HCl, clemastine fumarate,chlorothen citrate, chlorpheniramine maleate, dimethindene maleate,diphenhydramine HCl, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl(theruhistin), methapyrilene fumarate, methapyrilene HCl, montelukastsodium, phenindamine tartrate, pheniramine maleate, phenyltoloxaminecitrate, promethazine hydrochloride, prophenpyridamine maleate,pyrilamine maleate, thenyldiamine HCl, trimeprazine tartrate,tripelennamine HCl and triprolidine HCl.

Non-limiting examples of cough suppressants include, e.g., codeine,dihydrocodeine, hydrocodone, hydromorphone, dextromethorphan,carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine andpharmaceutically acceptable salts thereof such as, e.g., codeinephosphate, codeine sulfate, hydrocodone bitartrate, dihydrocodeinebitartrate, carbetapentane citrate and dextromethorphan hydrobromide.

Non-limiting examples of expectorants (including mucus thinning drugs)include guaifenesin and pharmaceutically acceptable salts thereof.

Non-limiting examples of analgesic and/or anti-inflammatory agentsinclude aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodiumnaproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, andfentanyl.

The term “pharmaceutically acceptable salts” as used herein refers tothose salts of a particular active ingredient that are not substantiallytoxic at the dosage administered to achieve the desired effect and donot independently possess significant pharmacological activity. Thesalts included within the scope of this term are pharmaceuticallyacceptable acid addition salts of a suitable inorganic or organic acid.Non-limiting examples of suitable inorganic acids are, for examplehydrochloric, hydrobromic, sulfuric and phosphoric acids. Non-limitingexamples of suitable organic acids include carboxylic acids, such asacetic, propionic, tannic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic,hydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic,anthranillic, cinnamic, salicylic, 4-aminosalicyclic, 2-phenoxybenzoic,2-acetoxybenzoic and mandelic acids, as well as sulfonic acids, such asmethanesulfonic, ethanesulfonic, and β-hydroxyethanesulfonic acids.

The optional additional active ingredients of the first and seconddosage units may vary between separate first dosage units. The sameapplies with respect to the presence of additional active ingredientsfor the second dosage units. In other words, the first (second) dosageunits may not all be the same and may differ, except thatpseudoephedrine is always included in the first dosage units andphenylephrine in the second dosage units. However, to simplifyadministration it will usually be preferred to provide a single firstdosage unit (e.g., a tablet, capsule, suspension, etc.) that containsall of the first active ingredients as well as a single second dosageunit (e.g., a tablet, capsule, suspension, etc.) that contains all ofthe second active ingredients.

The first dosage unit(s) and the second dosage unit(s) of thecombination of the present invention are adapted for oraladministration. The dosage forms for the first and second dosage unit(s)may be a solid form, for example, a dosage form selected from tablets,capsules, pills, caplets, powders and lozenges, or the first/seconddosage unit(s) may comprise a liquid or semi-liquid dosage form such as,e.g., a solution, a suspension, a syrup, or a gel. The dosage form ofthe first dosage unit(s) and the dosage form of the second dosageunit(s) may be the same or may be different. By way of non-limitingexample, the first and second dosage unit(s) may both be present insolid form, e.g., in the form of a tablet (e.g., a multilayered tablet),or the first and second dosage unit(s) may both be present in liquidform, e.g., in the form of a suspension. Also, the first (second) dosageunit(s) may be present in solid form, e.g., as a tablet, and the second(first) dosage unit(s) may be present in liquid form, e.g., as a syrup.

The active ingredients contained in the first and second dosage unitsmay be present in an immediate release dosage form and/or they may bepresent in a controlled release dosage form. The term “controlledrelease dosage form” as used herein and in the appended claims includesany dosage form that is not an immediate release dosage form, i.e., doesnot release the active ingredient contained therein within a relativelyshort period of time (for example, within less than about 1 hour, e.g.,less than about 0.5 hours following ingestion of the dosage form).Accordingly, this term is a generic term which encompasses, e.g.,sustained (extended) release dosage forms, pulsed release dosage forms,delayed release dosage forms, and the like. Preferably, the sustainedrelease dosage forms release the one or more active ingredientscontained therein steadily, in approximately equal amounts per timeunit, over an extended period of time such as, e.g., at least about 4hours, at least about 6 hours, at least about 8 hours, at least about 10hours, at least about 12 hours, at least about 14 hours, or at leastabout 16 hours. The desirable length of time period of continuous orintermittent (e.g., pulsed) release depends, inter alia, on the plasmahalf-life of the active ingredient and/or an active metabolite thereof.

It is to be appreciated that each of the first (second) dosage units maycomprise immediate release dosage forms and controlled release dosageforms at the same time. The same applies to the simultaneous presence oftwo or more different controlled release dosage forms in the first(second) dosage units. Different dosage forms can be present indifferent dosage units or may be combined in a single dosage unit suchas, a multilayered tablet, preferably, a bi-layered tablet. Non-limitingexamples of further suitable dosage units and of other optional and/orpreferred features of the combination of the present invention are setforth in, e.g., copending U.S. application Ser. Nos. 10/736,902,10/798,884, 10/910,806, 10/939,351, 11/012,267, 11/059,666, 11/102,725,11/102,726, 11/132,300, 11/115,321 and 11/115,293, the entiredisclosures whereof are expressly incorporated by reference herein.

For example, a multi-layered tablet for use in the present inventionwill comprise at least a first layer and a second layer, but mayoptionally comprise a third, fourth, fifth, etc. layer. The first layermay be an immediate release layer or a controlled release layer,depending on the active ingredient(s) contained therein and the desiredrelease characteristics thereof. The second layer may also be animmediate release layer or a controlled release layer, depending on theactive ingredient(s) contained therein and the desired releasecharacteristics thereof. If more than two active ingredients are to beincorporated in the tablet, the first and/or the second layer maycontain all of the active ingredients. Alternatively, separateadditional layers may be provided for the additional activeingredient(s), for example, in cases where it would be difficult todesign a controlled release layer which provides a desired release ratefor different active ingredients. Of course, a fourth, fifth, etc. layermay be provided for, e.g., a third or fourth additional activeingredient, and so on. Alternatively and by way of non-limiting example,the second and a third layer may contain the same active ingredient(s),but in different (relative) concentrations and/or incorporated in adifferent controlled release formulation.

A multi-layered tablet for use in the combination of the presentinvention will usually be made up of two or more distinct layers ordiscrete zones of granulation compressed together with the individuallayers lying on top of one another. Layered tablets have the appearanceof a sandwich because the edges of each layer or zone are visible. Suchconventional layered tablets are generally prepared by compressing agranulation onto a previously compressed granulation. The operation maybe repeated to produce multilayered tablets with more than two layers.

It is to be noted that it is not necessary for the two or moreindividual layers of the multilayered tablet to lie on top of oneanother. By way of non-limiting example, a second layer (e.g., sustainedrelease layer) may be partially or completely surrounded by a firstlayer (e.g., an immediate release layer). For example, the second layermay be coated with the first layer. In the case of three layers, forexample, the third layer may be partially or completely coated with thesecond layer, which in turn may be partially or completely coated withthe first layer. Of course, these are but a few examples of the manydifferent ways in which the various layers of a multilayered tablet foruse in the combination of the present invention can be arranged relativeto each other. Moreover, it is to be understood that tablets for use inthe present invention are not limited to multilayered tablets. By way ofnon-limiting example, the tablet may comprise an immediate releasematrix which comprises one or more first active ingredients, whichmatrix has dispersed therein particles of one or more sustained releaseformulations which have one or more active ingredients (which may thesame or different from those in the immediate release matrix)incorporated therein.

The simultaneous use of different dosage forms, e.g., immediate releaseand extended release dosage forms, for the first (second) dosage unitsmay, for example, be particularly advantageous in cases where one ormore of the active ingredients have a plasma half-life that differssignificantly (e.g., by several hours) from the plasma half-life of oneor more of the other active ingredients that are present in the first(second) dosage units. By using a different release profile for activeingredients with significantly different plasma half-life it is possibleto ensure that these active ingredients exhibit their therapeuticeffects over similar time periods.

The first and second layers of a dosage unit such as a bi-layered tabletfor use in the combination of the present invention will usually containthe pseudoephedrine or phenylephrine and the optional additional activeingredient(s) contained therein in amounts which are commensurate withthe intended duration of action but will not give rise to overdosingwhen present in the intended form (e.g., a particular pharmaceuticallyacceptable salt) and the intended release matrix (e.g., immediaterelease, controlled release, etc.). In this regard, it is noted that anyactive ingredient may be present in both the first layer and the secondlayer (and any additional layer, if present), for example, in order toobtain an as fast as possible release and, thus action of the activeingredient (e.g., by using an immediate release matrix) and to at thesame time extend the duration of the action of the active ingredient(e.g., by using a controlled release matrix that releases the drug at alower rate and/or at a later time than the immediate release layer). Inthe following, preferred ranges of amounts of selected activeingredients for use in a bi-layered tablet or any other dosage form foruse in the combination of the present invention are given forillustrative purposes only.

Promethazine: at least about 0.1 mg, e.g., at least about 5 mg, at leastabout 6 mg, at least about 8 mg, at least about 12 mg, or at least about25 mg, but not more than about 90 mg, e.g., not more than about 75 mg,not more than about 70 mg, not more than about 60 mg, or not more thanabout 50 mg of promethazine hydrochloride or an equivalent amount (on amolar basis) of promethazine and/or any other pharmaceuticallyacceptable salt thereof.

Chlorpheniramine: at least about 0.1 mg, e.g., at least about 2 mg, orat least about 4 mg, but not more than about 16 mg, e.g., not more thanabout 12 mg of chlorpheniramine maleate or an equivalent amount (on amolar basis) of chlorpheniramine and/or any other pharmaceuticallyacceptable salt thereof.

Carbinoxamine: at least about 0.1 mg, e.g., at least about 6 mg, but notmore than about 32 mg, e.g., not more than about 24 mg of carbinoxaminemaleate or an equivalent amount (on a molar basis) of carbinoxamineand/or any other pharmaceutically acceptable salt thereof.

Diphenhydramine: at least about 10 mg, e.g., at least about 15 mg, atleast about 20 mg, at least about 40 mg, at least about 70 mg, or atleast about 90 mg, but not more than about 200 mg, e.g., not more thanabout 150 mg, not more than about 120 mg, or not more than about 100 mgof diphenhydramine hydrochloride or an equivalent amount (on a molarbasis) of diphenhydramine and/or any other pharmaceutically acceptablesalt thereof.

Carbetapentane: at least about 1 mg, e.g., at least about 5 mg, at leastabout 10 mg, at least about 25 mg, or at least about 50 mg, but not morethan about 120 mg, e.g., not more than about 100 mg, not more than about70 mg, or not more than about 60 mg, of carbetapentane citrate or anequivalent amount (on a molar basis) of carbetapentane and/or any otherpharmaceutically acceptable salt thereof.

Codeine: at least about 1 mg, e.g., at least about 10 mg, at least about25 mg, or at least about 30 mg, but not more than about 120 mg, e.g.,not more than about 80 mg, not more than about 60 mg, or not more thanabout 45 mg, of codeine phosphate or an equivalent amount (on a molarbasis) of codeine and/or any other pharmaceutically acceptable saltthereof.

Dihydrocodeine: at least about 1 mg, e.g., at least about 5 mg, but notmore than about 30 mg, e.g., not more than about 20 mg, ofdihydrocodeine bitartrate or an equivalent amount (on a molar basis) ofdihydrocodeine and/or any other pharmaceutically acceptable saltthereof.

Hydrocodone: at least about 1 mg, e.g., at least about 5 mg, but notmore than about 20 mg, e.g., not more than about 15 mg, of hydrocodonebitartrate or an equivalent amount (on a molar basis) of hydrocodoneand/or any other pharmaceutically acceptable salt thereof.

Guaifenesin: at least about 1 mg, e.g., at least about 10 mg, at leastabout 25 mg, at least about 50 mg, or at least about 100 mg, but notmore than about 2400 mg, e.g., not more than about 1600 mg, not morethan about 1500 mg, not more than about 1200 mg, not more than about1000 mg, not more than about 600 mg, or not more than about 500 mg ofguaifenesin base or an equivalent amount (on a molar basis) of apharmaceutically acceptable salt thereof.

Acetaminophen: at least about 10 mg, e.g., at least about 50 mg, or atleast about 100 mg, but not more than about 1000 mg, e.g., not more thanabout 500 mg, or not more than about 250 mg of acetaminophen.

In a preferred aspect of the combination of the present invention, theone-time ingestion of one of the first and second dosage units providesrelief from the symptoms associated with respiratory ailments such as,e.g., nasal congestion for a period until it is time to take the otherone of the first and second dosage units. In other words, both the firstand second dosage units are preferably capable of providingtherapeutically effective plasma concentrations of the activeingredients contained therein over extended periods of time, forexample, for the first dosage units at least about 10 hours, at leastabout 12 hours, at least about 14 hours, at least about 16 hours or atleast 24 hours, and for the second dosage units at least about 8 hours,at least about 10 hours, or at least about 12 hours.

A preferred single first (pseudoephedrine) dosage unit (or a pluralityof dosage units to be ingested at once) will comprise a total of atleast about 30 mg, e.g., at least about 40 mg, at least about 50 mg, atleast about 60 mg, at least about 75 mg, at least about 80 mg, or atleast about 100 mg, but not more than about 140 mg, not more than about130 mg, or not more than about 120 mg of pseudoephedrine hydrochlorideor an equivalent amount (on a molar basis) of pseudoephedrine and/or anyother pharmaceutically acceptable salt thereof (e.g., pseudoephedrinetannate).

A preferred second (phenylephrine) dosage unit (or a plurality of seconddosage units to be ingested at once) will comprise a total of at leastabout 30 mg, e.g., at least about 40 mg, at least about 50 mg, at leastabout 60 mg, at least about 75 mg, but not more than about 90 mg, e.g.,not more than about 85 mg or not more than about 80 mg of phenylephrinehydrochloride or an equivalent amount (on a molar basis) ofphenylephrine and/or another pharmaceutically acceptable salt thereof(e.g., phenylephrine tannate).

The dosage units of the combination of the present invention can bemanufactured by processes which are well known to those of skill in theart. For example, for the manufacture of tablets the active ingredientsmay be dispersed uniformly into a mixture of excipients, for example, byhigh shear granulation, low shear granulation, fluid bed granulation, orby blending for direct compression.

Excipients may include diluents, binders, disintegrants, dispersants,lubricants, glidants, stabilizers, surfactants and colorants. Diluents,also termed “fillers”, are typically used to increase the bulk of atablet so that a practical size is provided for compression.Non-limiting examples of diluents include lactose, cellulose,microcrystalline cellulose, mannitol, dry starch, hydrolyzed starches,powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide,dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate,alumina and kaolin. Binders impart cohesive qualities to a tabletformulation and are used to ensure that a tablet remains intact aftercompression. Non-limiting examples of suitable binders include starch(including corn starch and pregelatinized starch), gelatin, sugars(e.g., glucose, dextrose, sucrose, lactose and sorbitol), celluloses,polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia,tragacanth, sodium alginate, and synthetic polymers such aspolymethacrylates and polyvinylpyrrolidone. Lubricants facilitate tabletmanufacture; non-limiting examples thereof include magnesium stearate,calcium stearate, stearic acid, glyceryl behenate, and polyethyleneglycol. Disintegrants facilitate tablet disintegration afteradministration, and non-limiting examples thereof include starches,alginic acid, crosslinked polymers such as, e.g., crosslinkedpolyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starchglycolate, clays, celluloses, starches, gums and the like. Non-limitingexamples of suitable glidants include silicon dioxide, talc and thelike. Stabilizers inhibit or retard drug decomposition reactions,including oxidative reactions. Surfactants may be anionic, cationic,amphoteric or nonionic. If desired, the tablets may also contain minoramounts of nontoxic auxiliary substances such as pH buffering agents,preservatives, e.g., antioxidants, wetting or emulsifying agents,solubilizing agents, coating agents, flavoring agents, and the like.

Extended/sustained release formulations may be made by choosing theright combination of excipients that slow the release of the activeingredients by coating or temporarily bonding or decreasing thesolubility of the active ingredients. Non-limiting examples of theseexcipients include cellulose ethers such as hydroxypropylmethylcellulose(e.g., Methocel K4M), polyvinylacetate-based excipients such as, e.g.,Kollidon SR, and polymers and copolymers based on methacrylates andmethacrylic acid such as, e.g., Eudragit NE 30D.

Several commercially available tablet presses are capable of makingtablets for use in the combination of the present invention.Non-limiting examples of presses for the manufacture of bi-layeredtablets include Manesty RotaPress Diamond; Fette America Model No.PT3090; Maneklal Global Exports Models JD and DH series; Niro PharmaSystems Model R292F; and Korsch AG Models XL 800 and XL400.

The one or more first dosage units and the one or more second dosageunits of the combination of the present invention are preferably held inseparate dispensing containers which in turn are preferably accommodatedin a single dispensing unit such as, e.g., a small box of the type thatis conventionally used for medicine that is sold over the counter. Ofcourse, the single dispensing unit may also take other forms such as,e.g., a plastic bag that contains two or more dispensing containers. Inanother non-limiting embodiment, the dispensing containers may be heldtogether by a plastic film such as, e.g., a shrink-wrap film.

The dispensing containers for the first and second dosage units of thecombination of the present invention may take various forms, forexample, conventional forms for pharmaceutical containers such as, e.g.,bottles, tubes, pouches, canisters and packets. Preferred, non-limitingexamples of dispensing containers include bottles and blister packages.Preferably, but not necessarily, the first and second dosage units willbe provided in the same type of dispensing container such as, e.g., in afirst bottle which accommodates the first dosage units and in a secondbottle which accommodates the second dosage units. It may sometimes bedesirable to provide more than one dispensing container for each type ofdosage unit (mainly depending on the quantity and size of the dosageunits to be provided in a single dispensing unit).

The first and second dosage units of the combination of the presentinvention will usually and preferably be rendered easilydistinguishable. Especially in the case of solid dosage forms such as,e.g., tablets, pills, capsules and the like, a convenient way of makingthe first and second dosage units distinguishable is by providing themwith a different color (e.g., yellow and blue) or a different shade,brightness, etc. of the same color (e.g., a lighter color tone fordaytime administration and a darker color tone for nighttimeadministration). Of course, one of skill in the art will be aware ofmany other ways that are suitable for rendering the different dosageunits distinguishable, for example, different sizes, different shapes,different indicia, different dosage forms (e.g., solid and liquid), etc.Also, two or more different ways of making the dosage unitsdistinguishable may be combined.

Alternatively or cumulatively, the dosage units may be madedistinguishable through the dispensing containers that accommodate them.As in the case of the dosage units themselves, the colors, shapes, sizesand types of the dispensing containers are non-limiting features thereofwhich provide particularly convenient means for making them readilydistinguishable.

Also, a dispensing container for the first dosage units and a dispensingcontainer for the second dosage units may have different indiciathereon. The use of different indicia is advantageous in that it notonly allows making the different dosage units distinguishable but alsoprovides a way of clearly and unambiguously indicating whether thedosage units are intended for daytime administration or for nighttimeadministration (e.g., by providing them with words such as “DAY” or“NIGHT” thereon). Of course, the dispensing containers may haveadditional information thereon, for example, information whichidentifies the particular day of the treatment regimen for which a givendosage unit is intended (e.g., “DAY 1”, “DAY 2”, etc.).

In addition to the first and second dosage units, the optionaldispensing containers and the optional dispensing unit whichaccommodates the containers, the combination of the present inventionmay comprise further components. In particular, the first and seconddosage units are preferably accompanied by instructions (e.g., labels)which instruct the patient as to which dosage units are to be taken fordaytime and which dosage units are to be taken for nighttime.Corresponding instructions will preferably also provide information asto how many dosage units are to be taken at a time (e.g., one dosageunit for children and two dosage units for adults, etc.), and in whichintervals. Further, the instructions may provide information as to therecommended number of days for which the dosage units should beingested.

The present invention also provides a regimen for the alleviation ofrespiratory ailments such as nasal congestion wherein the one or morefirst dosage units are administered to a subject in need thereof in anamount which is sufficient to maintain a therapeutically effectiveplasma level of pseudoephedrine over a first period, and wherein the oneor more second dosage units are administered to the subject in an amountwhich is sufficient to maintain a therapeutically effective plasma levelof pseudophedrine over a second period.

The first period of the regimen of the present invention substantiallycoincides with a period during which the subject intends to be awake(usually during the day, hereafter frequently referred to as beingsuitable/desirable “for daytime administration”, although it is to beappreciated that, for example, some people work during the night andsleep during the day wherefore they would have to take the first dosageunits for the nighttime period). The first dosage units for the firstperiod are preferably free of any substance that causes drowsiness in a(human) patient.

The second period of the regimen coincides with a period during whichthe patient intends to sleep (usually at least during the night,hereafter frequently referred to as being suitable/desirable “fornighttime administration”, although it is to be appreciated that, forexample, some people work during the night and sleep during the daywherefore they would have to take the second dosage units for thedaytime period. The second dosage units for the second period arepreferably free of any substance that causes nervous system stimulationin a (human) patient.

Preferably, the regimen of the present invention is designed so thatthere is substantially no overlap or gap between the first and secondperiods. For example, the first period will usually not overlap thesecond period by more than about 30 minutes, e.g., not more than about15 minutes, or not more than about 10 minutes. Also, a time gap betweenthe first and second periods will usually be not longer than about 30minutes, e.g., not longer than about 15 minutes or not longer than about10 minutes. Preferably, the first period and the second period togetherare about 24 hours long, wherein, in a preferred aspect, the firstperiod is from about 12 hours to about 16 hours long.

In the regimen, preferably a one-time administration of the one or morefirst dosage units is sufficient to maintain a therapeutically effectiveplasma level of pseudoephedrine over the entire first period. A minimumtherapeutically effective plasma level of pseudoephedrine is preferablynot substantially exceeded with the regimen of the present invention.For example, the plasma level of pseudoephedrine provided by the regimenof the present invention will preferably not be higher than about 150%,e.g., not higher than about 125%, not higher than about 110%, or nothigher than about 105% of the minimum therapeutically effective plasmalevel of pseudoephedrine. The same applies to the plasma level ofphenylephrine. Also preferred is a one time administration of the one ormore second dosage units to maintain a therapeutically effective plasmalevel of phenylephrine over the entire second period. Also in the caseof phenylephrine the minimum therapeutically effective plasma levelthereof is preferably not substantially exceeded with the regimen of thepresent invention. The administration of the one or more first dosageunits and the subsequent administration of the one or more second dosageunits is usually repeated at least once, e.g., at least 2 times, atleast 3 times, at least 4 times and generally as many times as necessaryfor the symptoms of the respiratory ailments to subside.

In another aspect of the regimen of the present invention, the periodfor the at least one additional active ingredient comprised in the firstand/or second dosage units overlaps with at least 70% of the firstperiod or of the second period. In other words, the first and seconddosage units which comprise one or more additional active ingredientsare preferably designed to provide a plasma concentration within thetherapeutic range of an additional active ingredient over a period whichis coextensive with at least about 70% of the period over which thedosage units provide a plasma concentration within the therapeutic rangeof pseudoephedrine or phenylephrine, respectively. For example, with thedosage units of the present invention, the plasma concentration withinthe therapeutic range of an additional active ingredient may becoextensive with at least about 80%, e.g., at least about 90%, or atleast about 95%, of the period of a plasma concentration within thetherapeutic range of pseudoephedrine or phenylephrine. The term“therapeutic range” refers to the range of drug levels (including activemetabolite levels) within which most patients will experience asignificant therapeutic effect (including alleviation of symptoms)without an undesirable degree of adverse reactions. The “minimumtherapeutically effective plasma level” is the minimum drug level(including active metabolite levels) within which most patients willexperience a significant therapeutic effect (including alleviation ofsymptoms) without an undesirable degree of adverse reactions. It isnoted that the term “coextensive with” does not exclude, but ratherincludes, cases where a part of the period over which the plasmaconcentration of a first drug (and/or active metabolites thereof) iswithin the therapeutic range is outside the period over which the plasmaconcentration of a second drug is within the therapeutic range.

The following non-limiting examples illustrate the present invention.

Example 1 A. Bi-Layered Tablet Comprising Pseudoephedrine for Day TimeAdministration

A bi-layered tablet which comprises pseudoephedrine tannate andchlorpheniramine tannate in an immediate release layer andcarbetapentane tannate in a sustained release layer is illustrated asfollows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Immediaterelease) Pseudoephedrine Tannate 60.0 85.7 Chlorpheniramine Tannate 8.011.4 Microcrystalline Cellulose 120.0 171.4 Povidone 9.5 13.6 SilicifiedMicrocrystalline Cellulose 100.0 142.9 Magnesium Stearate 2.5 3.6 Layer2 (Sustained release) Carbetapentane Tannate 30.0 42.9 MicrocrystallineCellulose (PH 102) 100.0 142.9 Lactose Monohydrate 44.5 63.6 MethocelK4M 50.0 71.4 Povidone 12.0 17.1 Methocel K4M 130.0 185.7 ColloidalSilicon Dioxide 1.0 1.4 Magnesium Stearate 2.5 3.6 Total 700.0 1000.0Process:

(a) Immediate release layer #1: Pseudoephedrine Tannate,Chlorpheniramine Tannate, Microcrystalline Cellulose are mixed in a highshear mixer/granulator for 10 minutes. The resultant blend is granulatedusing a 30% Povidone solution (13.6 g povidone in 45.3 g of finalsolution). Upon completion of the granulation process, the wet mass isdried until the LOD (loss on drying) is less than 2.0% and the granulesare screened through a USP sieve size #14. The granules with SilicifiedMicrocrystalline Cellulose are loaded into the V-blender and blended for10 minutes. Finally, prescreened Magnesium Stearate (through USP sieve#30) is loaded into the V shaped blender and blended for 3 minutes.

(b) Sustained release layer #2: Carbetapentane Tannate, MicrocrystallineCellulose PH 102, Lactose Monohydrate and Methocel K4M (1^(st) fraction)are mixed in a high shear mixer/granulator for 10 minutes. The resultantblend is granulated using a 30% Povidone solution (17.1 g Povidone in57.0 g of final solution). Thereafter the granulation is dried until theLOD is less than 2.0% and the granules are screened through a USP sievesize #14. The granules along with prescreened Colloidal Silicon Dioxide(through USP sieve size #30) and Methocel K4M (2^(nd) fraction) areloaded into a V-shaped blender and blended for 10 minutes. Finally,prescreened Magnesium Stearate (through USP sieve size #30) is loadedinto the V-shaped blender and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 300 mg and theweight of tablet layer #2 is about 400 mg. Capsules may be manufacturedby filling the same proportions into capsules.

B. Bi-Layered Tablet Comprising Phenylephrine for Night TimeAdministration

A bi-layered tablet which comprises phenylephrine tannate andchlorpheniramine tannate in an immediate release layer and phenylephrinetannate in a sustained release layer is illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Immediaterelease) Phenylephrine Tannate 60.0 85.7 Chlorpheniramine Tannate 8.011.4 Microcrystalline Cellulose PH 101 215.5 307.9 Povidone 14.0 20.0Magnesium Stearate 1.0 1.0 Layer 2 (Sustained release) PhenylephrineTannate 30.0 42.9 Microcrystalline Cellulose (PH 101) 100.0 142.9Calcium Phosphate Dihydrate 30.0 42.9 Povidone 15.0 21.4 METHOCEL K4M200.0 285.7 Stearic Acid 22.0 31.4 Magnesium Stearate 3.0 4.3 Total700.0 1000.0Procedure:

(a) Immediate release layer #1: Phenylephrine Tannate, ChlorpheniramineTannate, Microcrystalline Cellulose PH 101 are mixed in a high shearmixer/granulator for 10 minutes. The resultant blend is granulated usinga 30% Povidone solution (20.0 g Povidone in 66.7 g of solution). Uponcompletion of the granulation process, the wet mass is dried until theLOD is less than 2.0% and the granules are screened through a USP sievesize #14. The granules and prescreened Magnesium Stearate (through USPsieve size #30) are added into a V shaped blender and blended for 3minutes.

(b) Sustained release layer #2: Phenylephrine tannate, MicrocrystallineCellulose PH 101, Calcium Phosphate Dihydrate and Methocel K4M are mixedin a high shear mixer/granulator for 10 minutes. The obtained blend isgranulated by using a 30% povidone solution (21.4 g povidone in 71.3 gof solution). Thereafter the wet mass is dried until the LOD is lessthan 2.0%, and the granules are screened through a US sieve size #14.The granules and prescreened Stearic Acid (through USP sieve size #30)are loaded into a V-shaped blender and blended for 10 minutes; finallyprescreened Magnesium Stearate (through USP sieve size #30) is loadedinto the V-shaped blender and blended for 3 minutes.

Bi-layered tablets are manufactured by using a rotary bi-layer tabletpress, wherein the amount of tablet layer #1 is about 300 mg and theamount of tablet layer #2 is about 400 mg. Capsules may be manufacturedby filling the same proportions into capsules.

Example 2 A. Extended Release Suspension Comprising Pseudoephedrine forDay Time Administration

An extended release suspension which comprises a codeine phosphateion-exchange complex, pseudoephedrine tannate and chlorpheniraminetannate is illustrated as follows:

Ingredients Amount/5 ml Codeine Phosphate Ion- Equivalent to 45 mg ofExchange Complex Codeine Phosphate Pseudoephedrine Tannate 75.0 mgChlorpheniramine Tannate 4.5 mg Eudragit ® L 100 0.2 to 2.8 g Silica,colloidal anhydrous, NF 100 mg Glycerin 740 mg Xylitol, NF 800 mg SodiumCitrate, USP 100 mg Saccharin Sodium cryst., USP, 0.1 mg Sodium Benzoate7.5 mg Citric Acid Monohydrate, USP 8.0 mg Artificial Grape Flavor 5 mgFD&C Red #40 Dye 0.5 mg Water q.sProcedure for 1000 kg Batch:

Sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) is added to aCodeine Phosphate solution and the mixture is stirred for 12 hours toallow complete drug/resin complex formation. Then the insolubledrug/resin complex is separated and dried. The drug/resin complex isgranulated with a delayed release/enteric polymer (e.g. Eudragit® L 100,Kollidon® MAE, Aquacoat® CPD) and the granules are dried. If needed, thegranules may be milled.

In a suitably sized stainless steel vessel saccharin sodium, sodiumbenzoate, citric acid, and sodium citrate are dissolved in approximately50 L of warm (about 45° C.) purified water. In another large stainlesssteel drum silica, codeine phosphate ion-exchange complex,pseudoephedrine tannate and chlorpheniramine tannate are mixed withglycerin until a uniform and consistent mixture is obtained. In aseparate 1000 L stainless steel tank which is equipped with a suitablysized homogenizer/disperser about 100 L of purified water is added. Withthe homogenizer on, the silica mixture containing codeine phosphateion-exchange complex, pseudoephedrine tannate and chlorpheniraminetannate is added to the stainless steel tank. Next, a previouslyprepared solution of saccharin sodium, sodium benzoate, citric acid, andsodium citrate is added to the tank. The first vessel is rinsed withabout 2 L of water and the rinsate is transferred to the 1000 L tank.Finally, the remaining ingredients are added and homogenized for 15minutes.

B. Extended Release Suspension Comprising Phenylephrine for Night TimeAdministration

An extended release suspension which contains a hydrocodone bitartrateion-exchange complex, a dexchlorpheniramine maleate ion-exchange complexand a phenylephrine hydrochloride ion-exchange complex is illustrated asfollows:

Ingredients Amount/5 ml Hydrocodone Bitartrate Ion- Equivalent to 8 mgof Exchange Complex Hydrocodone Bitartrate Dexchlorpheniramine MaleateIon- Equivalent to 6 mg of Exchange Complex Dexchlorpheniramine MaleatePhenylephrine HCl Ion- Equivalent to 10 mg of Exchange ComplexPhenylephrine HCl Eudragit ® L 100 0.2 to 2.8 g Glycerin 315 mgPolysorbate 80 1.5 mg Carbomer (e.g., Carbopol ® 974) 15 mg MethylParaben 9 mg Propyl Paraben 1 mg Artificial Grape Flavor 5 mg FD&C Red#40 Dye 0.5 mg Water q.s

The formula described above serves as a non-limiting example. Any activedrug which is in the form of a salt, such as an antihistamine, codeine,or dihydrocodeine, can be incorporated as an ion-exchange resin complex.

Procedure:

Sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) is added to asolution of dexchlorpheniramine maleate, hydrocodone bitartrate andphenylephrine HCl and the mixture is stirred for 12 hrs to allowcomplete drug/resin complex formation. The resultant insolubledrug/resin complex is separated and dried. The drug/resin complex isgranulated with a delayed release/enteric polymer (e.g. Eudragit® L 100,Kollidon® MAE, Aquacoat® CPD) and the granules are dried. If needed, thegranules may be milled. Next, in an appropriate amount of water thefollowing ingredients are dissolved: Carbomer (e.g., Carbopol® 974),glycerin, polysorbate 80, methyl paraben, propyl paraben, artificialgrape flavor, FD&C red #40 dye. To this suspension the milled granulesare added as well as more water to make up to a final volume. To avoidsettling of the suspension and to maintain a homogeneous product mixtureagitation at a suitable rate has to be maintained. The product is filledin suitable containers ensuring that the product is homogeneousthroughout the filling operation.

Example 3 A. Extended Release Suspension Comprising Pseudoephedrine forDay Time Administration

An extended release suspension which contains a carbetapentane citrateion-exchange complex, pseudoephedrine tannate and chlorpheniraminetannate is illustrated as follows:

Ingredients Amount/5 ml Carbetapentane Citrate Ion- Equivalent to 20 mgof Exchange Complex Carbetapentane Citrate Pseudoephedrine Tannate 75.0mg Chlorpheniramine Tannate 4.5 mg Eudragit ® L 100 0.2 to 2.8 g Silica,colloidal anhydrous, NF 100 mg Glycerin 740 mg Xylitol, NF 800 mg SodiumCitrate, USP 100 mg Saccharin Sodium cryst., USP, 0.1 mg Sodium Benzoate7.5 mg Citric Acid Monohydrate, USP 8.0 mg Artificial Grape Flavor 5 mgFD&C Red #40 Dye 0.5 mg Water q.sProcedure for 1000 kg Batch:

Sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69 or Amberlite®188N) is added to a carbetapentane citrate solution. Stir the mix for 12hrs to allow complete drug/resin complex formation. The resultantinsoluble drug/resin complex is separated and dried. The drieddrug/resin complex is granulated with a delayed release/enteric polymer(e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and the resultantgranules are dried. If needed, the granules may be milled. In a suitablysized stainless steel vessel saccharin sodium, sodium benzoate, citricacid monohydrate, sodium citrate and Xylitol are dissolved inapproximately 50 L of warm (about 45° C.) purified water. In anotherlarge stainless steel drum the silica, carbetapentane citrateion-exchange complex, pseudoephedrine tannate and the chlorpheniraminetannate are mixed with Glycerin until a uniform and consistent mixtureis obtained. In a separate 1000 L stainless steel tank which is equippedwith a suitably sized homogenizer/disperser about 100 L of purifiedwater is added. With the homogenizer on, the silica mixture containingcarbetapentane citrate ion-exchange complex, pseudoephedrine tannate andthe chlorpheniramine tannate is added to the stainless steel tank. Next,a previously prepared solution of saccharin sodium, sodium benzoate,citric acid, and sodium citrate are added to the tank. The first vesselis rinsed with about 2 L of water and the rinsate is transferred to the1000 L tank. Finally, the remaining ingredients are added andhomogenized for 15 minutes.

B. Extended Release Suspension Containing Phenylephrine for Night TimeAdministration

An extended release suspension which contains a hydrocodone bitartrateion-exchange complex, a dexchlorpheniramine maleate ion-exchange complexand a phenylephrine hydrochloride ion-exchange complex is illustrated asfollows:

Ingredients Amount/5 ml Hydrocodone Bitartrate Ion- Equivalent to 8 mgof Exchange Complex Hydrocodone Bitartrate Dexchlorpheniramine MaleateIon- Equivalent to 6 mg of Exchange Complex Dexchlorpheniramine MaleatePhenylephrine HCl Ion- Equivalent to 10 mg of Exchange ComplexPhenylephrine HCl Eudragit ® L 100 0.2 to 2.8 g Glycerin 315 mgPolysorbate 80 1.5 mg Carbomer (e.g., Carbopol ® 974) 15 mg MethylParaben 9 mg Propyl Paraben 1 mg Artificial Grape Flavor 5 mg FD&C Red#40 Dye 0.5 mg Water q.s

The formula described above serves as a non-limiting example. Any activedrug which is in the form of a salt, such as an antihistamine, codeine,or dihydrocodeine, can be incorporated as an ion-exchange resin complex.

Procedure:

Sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) is added to asolution of dexchlorpheniramine maleate, hydrocodone bitartrate andphenylephrine HCl and the mixture is stirred for 12 hrs to allowcomplete drug/resin complex formation. The resultant insolubledrug/resin complex is separated and dried. The dried drug/resin complexis granulated with a delayed release/enteric polymer (e.g. Eudragit® L100, Kollidon® MAE, Aquacoat® CPD) and the granules are dried. Ifneeded, the granules may be milled. Next, in an appropriate amount ofwater the following ingredients are dissolved: Carbomer (e.g., Carbopol®974), glycerin, polysorbate 80, methyl paraben, propyl paraben,artificial grape flavor, FD&C red #40 dye. To this suspension the milledgranules are added as well as more water to make up to a final volume.To avoid settling of the suspension and to maintain a homogeneousproduct mixture agitation at a suitable rate has to be maintained. Theproduct is filled in suitable containers.

Example 4 A. Bi-Layered Tablet Comprising Pseudoephedrine for Day TimeAdministration

A bi-layered tablet which comprises carbetapentane citrate in animmediate release layer and carbetapentane citrate, pseudoephedrinehydrochloride and chlorpheniramine maleate in a sustained release layeris illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Immediaterelease) Carbetapentane Citrate 10.0 16.7 Microcrystalline Cellulose PH101 140.0 233.1 Povidone 7.5 12.5 Silicified Microcrystalline Cellulose90.0 150.0 Magnesium Stearate 2.5 4.2 Layer 2 (Sustained release)Carbetapentane Citrate 40.0 66.7 Pseudoephedrine HCl 60.0 100.0Chlorpheniramine Maleate 8.0 13.3 Microcrystalline Cellulose (PH 102)87.0 145.0 Calcium Phosphate Dihydrate 20.0 33.3 Povidone 11.0 18.3Methocel K4M 120.0 200.0 Colloidal Silicon Dioxide 1.2 2.0 MagnesiumStearate 2.8 4.7 Total 600.0 1000.0Procedure:

(a) Immediate release layer #1: Carbetapentane Citrate andMicrocrystalline Cellulose PH 101 are blended in a high shearmixer/granulator for 10 minutes, the resulting blend is granulated usinga 30% Povidone solution (12.5 g Povidone in 41.7 g of solution). Thegranulation is dried until the LOD is less than 2.0%, followed by thestep of screening the granules through a USP sieve size #14. Thegranules and the Silicified Microcrystalline Cellulose are loaded intothe V-shaped blender and blended for 10 minutes. Finally, prescreenedmagnesium stearate (though USP sieve #30) is loaded into the V-shapedblender and blended for 3 minutes.

(b) Sustained release layer #2: Pseudoephedrine Hydrochloride,Chlorpheniramine Maleate, Carbetapentane Citrate, MicrocrystallineCellulose PH 101, Calcium Phosphate Dihydrate and Methocel K4M areblended in a high shear mixer/granulator for 10 minutes. The obtainedblend is granulated using a 30% Povidone solution (18.3 g Povidone in61.0 g of solution) and dried until the LOD is less than 2.0%. Thegranules are screened through a USP sieve size #14 and then addedtogether with prescreened Colloidal Silicon Dioxide (through USP sieve#30) to the V-shaped blender and blended for 10 minutes, prescreenedMagnesium Stearate (through USP sieve #30) and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress, wherein the weight of the immediate release tablet layer is about250 mg and the weight of the sustained release tablet layer is about 350mg.

B. Bi-Layered Tablet Comprising Phenylephrine for Night TimeAdministration

A bi-layered tablet which comprises phenylephrine hydrochloride andcarbinoxamine maleate in a first sustained release layer and codeinephosphate in a second sustained release layer is illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Sustainedrelease) Phenylephrine HCl 75.0 185.2 Carbinoxamine Maleate 8.0 19.8Methocel K4M 59.0 145.7 Microcrystalline Cellulose PH 101 30.0 74.1Eudragit NE 30 D 15.0 37.0 Magnesium Stearate 3.0 7.4 Layer 2 (Sustainedrelease) Codeine Phosphate 30.0 74.1 Microcrystalline Cellulose (PH 101)45.0 111.1 Methocel K4M 60.0 148.1 Eudragit NE 30 D 15.0 37.0 MethocelK4M 40.0 98.8 Stearic Acid 23.0 56.8 Magnesium Stearate 2.0 4.9 Total405.0 1000.0Procedure:

(a) Sustained release layer #1: Phenylephrine HCl, CarbinoxamineMaleate, Methocel K4M and Microcrystalline Cellulose PH 101 are mixed ina high shear mixer/granulator for 10 minutes. The resultant blend isgranulated using Eudragit NE 30 D (30% of solids in aqueous suspension(w/w)). Upon completion of the granulation process, the wet mass isdried until the LOD is less than 2.0% and the granules are screenedthrough a USP sieve size #14. The granules and prescreened MagnesiumStearate (through USP sieve size #30) are added to a V shaped blenderand are mixed for 3 minutes.

(b) Sustained release layer #2: Codeine Phosphate, MicrocrystallineCellulose PH 102, and Methocel K4M (1^(st) fraction) are mixed in a highshear mixer/granulator for 10 minutes. The obtained blend is granulatedusing Eudragit NE 30 D (30% solids in aqueous suspension (w/w)) followedby the addition of Methocel K4M into the granulator and post mixed for 1minute. The granulation is dried until the LOD is less than 2.0% and thegranules are screened through a USP sieve size #14. Prescreened StearicAcid (USP sieve size #30) is added to the V-shaped blender and blendedfor 10 minutes. Finally, prescreened Magnesium Stearate (USP sieve size#30) is loaded into the V-shaped blender and blended for additional 3minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 190 mg and theweight of tablet layer #2 is about 215 mg. Capsules may be manufacturedby filling the same proportions into capsules.

Example 5 A. Bi-Layered Tablet Comprising Pseudoephedrine for Day TimeAdministration

A bi-layered tablet which comprises pseudoephedrine hydrochloride andchlorpheniramine maleate in a first sustained release layer and codeinephosphate in a second sustained release layer is illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Sustainedrelease) Pseudoephedrine HCl 120.0 252.7 Chlorpheniramine Maleate 12.025.3 Methocel K4M 70.0 147.4 Silicified Microcrystalline Cellulose 35.073.7 Eudragit NE 20.0 42.1 Magnesium Stearate 3.0 6.3 Layer 2 (Sustainedrelease) Codeine Phosphate 30.0 63.2 Microcrystalline Cellulose (PH 101)45.0 94.7 Methocel K4M 70.0 147.3 Eudragit NE 30 D 15.0 31.6 MethocelK4M 30.0 63.2 Stearic Acid 22.5 47.4 Magnesium Stearate 2.5 5.3 Total475.0 1000.0Procedure:

(a) Sustained release layer #1: Pseudoephedrine HCl, ChlorpheniramineMaleate, Methocel K4M and Silicified Microcrystalline Cellulose aremixed in a high shear mixer/granulator for 10 minutes. The obtainedblend is granulated using Eudragit® NE 30 D (30% of solids in aqueoussuspension (w/w)). The resultant granulation mixture is dried until theLOD is less than 2.0% and then screened through a USP sieve size #14.Finally, the granules and prescreened Magnesium Stearate (through USPsieve size #30) are added into a V shaped blender and blended for 3minutes.

(b) Sustained release layer #2: Codeine Phosphate, Microcrystallinecellulose PH 101 and Methocel K4M (1^(st) fraction) are mixed in a highshear mixer/granulator for 10 minutes. The obtained blend is granulatedusing Eudragit NE 30 D (30% of solids in aqueous suspension (w/w)).Next, Methocel K4M (2′ fraction) is added to the granulator and postmixed for 1 minute. The granulation is dried until the LOD is less than2.0% and the granules are screened through a USP sieve size #14.Finally, the granules and prescreened Stearic Acid (through USP sievesize #30) are loaded into a V shaped blender and blended for 10 minutes;finally, prescreened Magnesium Stearate (through USP sieve size #30) isadded to the V shaped blender and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 260 mg and theweight of tablet layer #2 is about 215 mg. Capsules may be manufacturedby filling the same proportions into capsules.

B. Bi-Layered Tablet Comprising Phenylephrine for Night TimeAdministration

A bi-layered tablet which comprises guaifenesin in a first sustainedrelease layer and codeine phosphate, guaifenesin and phenylephrinehydrochloride in a second sustained release layer is illustrated asfollows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Sustainedrelease) Guaifenesin 400.0 363.6 Methocel K4M 100.0 90.9Microcrystalline Cellulose PH 101 40.0 36.4 Eudragit NE 30 D 42.0 38.2Silicified Microcrystalline cellulose 32.5 29.5 Magnesium Stearate 5.55.0 Layer 2 (Sustained release) Codeine Phosphate 30.0 27.3 Guaifenesin200.0 181.8 Phenylephrine HCl 60.0 54.6 Microcrystalline Cellulose PH101 45.0 40.9 Eudragit NE 30 D 45.0 40.9 Methocel K4M 50.0 45.5 MethocelK4M 25.0 22.7 Stearic Acid 20.0 18.2 Magnesium Stearate 5.0 4.7 Total1100.0 1000.0Procedure:

(a) Sustained release layer #1: Guaifenesin, Methocel K4M andMicrocrystalline Cellulose PH 101 are mixed in a high shearmixer/granulator for 10 minutes. The obtained blend is granulated usingEudragit® NE (30% of solids in aqueous suspension (w/w)). Next, thegranulation mixture is dried until the LOD is less than 2.0% and thenscreened through a USP sieve size #14. The granules and SilicifiedMicrocrystalline Cellulose are loaded into a V-shaped blender andblended for 10 minutes; finally, prescreened Magnesium Stearate (throughUSP sieve size #30) is added in the V shaped blender and blended for 3minutes.

(b) Sustained release layer #2: Codeine Phosphate, Guaifenesin,Phenylephrine HCl, Microcrystalline Cellulose PH 101 and Methocel K4M(1^(st) fraction) are mixed in a high shear mixer/granulator for 10minutes. The obtained blend is granulated using Eudragit NE 30 D (30% ofsolids in aqueous suspension (w/w)). Next, Methocel K4M (2^(nd)fraction) is added to the granulator and post mixed for 1 minute. Thegranulation is dried until the LOD is less than 2.0% and the granulesare screened through a USP sieve size #14. The granules and prescreenedStearic Acid (through USP sieve size #30) are loaded into a V-shapedblender and blended for 10 minutes; finally, prescreened MagnesiumStearate (through USP sieve size #30) is added to the V shaped blenderand blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 620 mg and theweight of tablet layer #2 is about 480 mg. Capsules may be manufacturedby filling the same proportions into capsules.

Example 6 A. Bi-Layered Tablet Comprising Pseudoephedrine for Day TimeAdministration

A bi-layered tablet which comprises promethazine hydrochloride in animmediate release layer and codeine phosphate and pseudoephedrinehydrochloride in a sustained release layer is illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Immediaterelease) Promethazine HCl 25.0 38.5 Microcrystalline Cellulose PH 101120.0 184.6 Povidone 8.0 12.3 Silicified microcrystalline cellulose 85.0130.8 Magnesium Stearate 2.0 3.1 Layer 2 (Sustained release) CodeinePhosphate 30.0 46.2 Pseudoephedrine HCl 120.0 184.6 MicrocrystallineCellulose (PH 101) 73.0 112.3 Calcium Phosphate Dihydrate 8.0 12.3Eudragit RS 30 D 25.0 38.5 Methocel K4M 90.0 138.4 Methocel K4M 45.069.2 Stearic Acid 15.0 23.1 Magnesium Stearate 4.0 6.2 Total 650.01000.0Procedure:

(a) Immediate release layer #1: Promethazine HCl and MicrocrystallineCellulose #101 are mixed in a high shear mixer/granulator for 10minutes. The resultant blend is granulated using a 30% Povidone solution(12.3 g Povidone in 41.0 g solution). Upon completion of the granulationprocess, the wet mass is dried until the LOD is less than 2.0% and thegranules are screened through a USP sieve size #14. The granules andSilicified Microcrystalline Cellulose are loaded into a V-shaped blenderand blended for 10 minutes; prescreened Magnesium Stearate is then addedto the V shaped blender and blended for 3 minutes.

(b) Sustained release layer #2: Codeine Phosphate, Pseudoephedrine HCl,Microcrystalline Cellulose PH 101, Calcium Phosphate Dihydrate, MethocelK4M (1^(st) fraction) are mixed in a high shear mixer/granulator for 10minutes. The obtained blend is granulated using Eudragit RS 30 D (30%solids in aqueous suspension (w/w)). Next, Methocel K4M is added to thegranulator and post mixed for 1 minute. The resultant granulation isdried until the LOD is less than 2.0% and the granules are screenedthrough a USP sieve size #14. The granules and prescreened Stearic Acid(USP sieve size #30) are loaded into a V shaped blender and blended for10 minutes. Finally, prescreened Magnesium Stearate (through USP sievesize #30) is then added and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 240 mg and theweight of tablet layer #2 is about 410 mg. Capsules may be manufacturedby filling the same proportions into capsules.

B: Bi-Layered Tablet Comprising Phenylephrine for Night TimeAdministration

A bi-layered tablet, which comprises codeine phosphate andchlorpheniramine maleate in a first sustained release layer andphenylephrine hydrochloride in a second sustained release layer isillustrated as follows:

Weight/tablet Weight/1 kg batch Ingredients (mg) (in grams) Layer 1(Sustained release) Codeine Phosphate 30.0 66.7 Chlorpheniramine Maleate8.0 17.8 Methocel K100M 30.0 66.7 Methocel E4M 20.0 44.4 SilicifiedMicrocrystalline 80.0 177.8 Cellulose Stearic Acid 2.0 4.4 SilicifiedMicrocrystalline 26.0 57.8 Cellulose Colloidal Silicon Dioxide 2.0 4.4Magnesium Stearate 2.0 4.4 Layer 2 (Sustained release) Phenylephrine HCl60.0 133.3 Methocel K100M 40.0 88.9 Methocel E4M 25.0 55.6 SilicifiedMicrocrystalline 100.0 222.2 Cellulose Stearic Acid 2.5 5.6 SilicifiedMicrocrystalline 17.5 38.9 Cellulose Colloidal Silicon Dioxide 2.5 5.6Magnesium Stearate 2.5 5.6 Total 450.0 1000.0Procedure:

(a) Codeine Phosphate and Chlorpheniramine Maleate are screened throughUSP sieve size #16: Prescreened materials along with Methocel K100M andMethocel E4M are loaded into a V-shaped blender and blended for 12minutes. Then Silicified Microcrystalline Cellulose (1^(st) fraction) isloaded into the V-shaped blender and blended for 5 minutes. Then,prescreened Stearic Acid, Silicified Microcrystalline Cellulose andColloidal Silicon Dioxide (through USP sieve size #30) are loaded intothe V-shaped blender and blended for 8 minutes. Finally prescreenedMagnesium Stearate (through USP sieve size #30) is loaded into theV-shaped blender and blended for 3 minutes.

(b) Phenylephrine Hydrochloride is screened through USP sieve size #16,then is loaded with Methocel K100M and Methocel E 4M into a V-shapedblender and blended for 12 minutes, Silicified MicrocrystallineCellulose (1^(st) fraction) is loaded and blended for 5 minutes. Then,prescreened Stearic acid, Silicified Microcrystalline Cellulose (2^(nd)fraction) and Colloidal Silicon Dioxide (through USP sieve size #30) areloaded into the V-shaped blender and blended for 8 minutes. Finally,prescreened Magnesium Stearate (through USP sieve size #30) is loadedinto the V-shaped blender and blended for 3 minutes.

(c) Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 200 mg and theweight of the layer #2 is about 250 mg. Capsules may be manufactured byfilling the same proportions into capsules.

Example 7 A. Bi-Layered Tablet Comprising Pseudoephedrine for Day TimeAdministration

A bi-layered tablet which comprises codeine phosphate in an immediaterelease layer; and codeine phosphate, pseudoephedrine hydrochloride andchlorpheniramine maleate in a sustained release layer for day timeadministration is illustrated as follows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Immediaterelease) Codeine Phosphate 10.0 20.0 Microcrystalline Cellulose 80.0160.0 PH 101 Povidone 4.5 9.0 Silicified Microcrystalline 103.5 207.0Cellulose Magnesium Stearate 2.0 4.0 Layer 2 (Sustained release) CodeinePhosphate 30.0 60.0 Pseudoephedrine HCl 60.0 120.0 ChlorpheniramineMaleate 8.0 16.0 Microcrystalline Cellulose 80.0 160.0 PH 101 MethocelK4M 70.0 140.0 Povidone 15.0 30.0 Methocel K4M 30.0 60.0 Stearic Acid3.5 7.0 Magnesium Stearate 3.5 7.0 Total 500.0 1000.0Procedure:

(a) Immediate release layer #1: Codeine Phosphate and MicrocrystallineCellulose PH 101 are blended in a high shear mixer/granulator for 10minutes. The resultant blend is granulated using a 30% Povidone solution(9.0 g Povidone in 30.0 g of solution). The resultant granulation isdried until the LOD is less than 2.0% and the granules are screenedthrough a USP sieve size #14. Granules and Silicified MicrocrystallineCellulose are loaded into a V-shaped blender and blended for 10 minutes.Finally, prescreened Magnesium Stearate (through USP sieve size #30) isloaded and blended in the V-shaped blender for 3 minutes.

(b) Sustained release layer #2: Codeine Phosphate, PseudoephedrineHydrochloride, Chlorpheniramine Maleate, Microcrystalline Cellulose PH101 and Methocel K4M (1^(st) fraction) are blended in a high shearmixer/granulator for 10 minutes. The resultant blend is granulated usinga 30% Povidone solution (30.0 g Povidone in 100.0 g of solution). Next,Methocel K4M (2^(nd) fraction) is added to the granulator and postmixedfor 1 minute. The resultant granulation is dried until the LOD is lessthan 2.0% and the granules are screened through a USP sieve size #14.The granules and prescreened Stearic Acid (USP sieve size #30) areloaded into a V-shaped blender and blended for 10 minutes. Finally,prescreened Magnesium Stearate (through USP sieve size #30) is loadedinto the V-shaped blender and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress, wherein the weight of tablet layer #1 is about 200 mg and theweight of tablet layer #2 is about 350 mg.

B. Bi-Layered Tablet Containing Phenylephrine for Night TimeAdministration

A bi-layered tablet which comprises guaifenesin in a first sustainedrelease layer; and codeine phosphate, phenylephrine hydrochloride andguaifenesin in a second sustained release layer is illustrated asfollows:

Weight/tablet Weight/1 kg Ingredients (mg) batch (g) Layer 1 (Sustainedrelease) Guaifenesin 600.0 428.6 Microcrystalline Cellulose PH 101 35.025.0 Methocel K4M 50.0 35.7 Eudragit NE 30 D 35.0 25.0 Methocel K4M 20.014.3 Stearic acid 5.0 3.6 Magnesium Stearate 5.0 3.6 Layer 2 (Sustainedrelease) Guaifenesin 400.0 285.7 Codeine Phosphate 30.0 21.4Phenylephrine HCl 60.0 42.9 Microcrystalline Cellulose PH 101 30.0 21.4Methocel K4M 50.0 35.7 Eudragit NE 30 D 30.0 21.4 Methocel K4M 25.0 17.9Methocel K4M 16.0 11.4 Stearic Acid 3.0 2.1 Magnesium Stearate 6.0 4.3Total 1400.0 1000.0Procedure:

(a) Sustained release layer #1: Guaifenesin, Microcrystalline CellulosePH 101 and Methocel K4M (1^(st) fraction) are blended in a high shearmixer/granulator for 10 minutes. The resultant blend is granulated usinga Eudragit NE 30 D suspension (30% of solids in aqueous suspension(w/w)) followed by the addition of Methocel K4M (2^(nd) fraction) andpostmixed for 1 minute. The granulation is dried until the LOD is lessthan 2.0% and the granules are screened through a USP sieve size #14.The granules and prescreened Stearic Acid (through a USP sieve size #30)are loaded into a V-shaped blender and blended for 10 minutes. Finally,prescreened Magnesium Stearate (through a USP sieve size #30) is loadedin the V shaped blender and blended for 3 minutes.

(b) Sustained release layer #2: Remaining Guaifenesin (equivalent to 400mg/tablet), Codeine Phosphate, Phenylephrine Hydrochloride,Microcrystalline Cellulose PH 101 and Methocel K4M (1^(st) fraction) aremixed in a high shear mixer/granulator for 10 minutes. The resultantblend is granulated using a Eudragit NE 30 D suspension (30% of solidsin aqueous suspension (w/w)), followed by the addition of Methocel K4M(2^(nd) fraction) and postmixed for 1 minute. The granulation is drieduntil the LOD is less than 2.0% and the granules are screened through aUSP sieve size #14. The granules, Methocel K4M (3^(rd) fraction) andprescreened Stearic Acid (through USP sieve size #30) are loaded into aV-shaped blender and blended for 10 minutes. Finally, prescreenedMagnesium Stearate (through USP sieve size #30) is loaded to the Vshaped blender and blended for 3 minutes.

Bi-layered tablets are manufactured using a rotary bi-layer tabletpress; wherein the weight of tablet layer #1 is about 750 mg and theweight of tablet layer #2 is 650 mg. Capsules may be manufactured byfilling the same proportions into capsules.

It is noted that the foregoing examples have been provided merely forthe purpose of explanation and are in no way to be construed as limitingof the present invention. While the present invention has been describedwith reference to exemplary embodiments, it is understood that the wordswhich have been used herein are words of description and illustration,rather than words of limitation. Changes may be made, within the purviewof the appended claims, as presently stated and as amended, withoutdeparting from the scope and spirit of the present invention in itsaspects. Although the present invention has been described herein withreference to particular means, materials and embodiments, the presentinvention is not intended to be limited to the particulars disclosedherein; rather, the present invention extends to all functionallyequivalent structures, methods and uses, such as are within the scope ofthe appended claims.

What is claimed is:
 1. A combination of oral dosage units foralleviating respiratory ailments, wherein the combination comprises: (a)one or more first dosage units which comprise at least one ofpseudoephedrine and a pharmaceutically acceptable salt thereof; and (b)one or more second dosage units which comprise at least one ofphenylephrine and a pharmaceutically acceptable salt thereof; andwherein the first and second dosage units are different and separatefrom each other and at least one of the first and second dosage units atleast one of (i) comprises an antihistamine, (ii) is free of anexpectorant and (iii) is free of a cough suppressant.
 2. The combinationof claim 1, wherein at least one of the first and second dosage unitsfurther comprises at least one of an antihistamine, a cough suppressant,an expectorant, an analgesic and an anti-inflammatory agent.
 3. Thecombination of claim 2, wherein the first and second dosage units eachindependently comprise at least one of an antihistamine, a coughsuppressant, an expectorant, an analgesic and an anti-inflammatoryagent.
 4. The combination of claim 2, wherein at least one of the firstand second dosage units comprises at least one of an antihistamine and acough suppressant.
 5. The combination of claim 3, wherein the first andsecond dosage units each independently comprise at least one of anantihistamine and a cough suppressant.
 6. The combination of claim 3,wherein at least one of the first and second dosage units comprises anantihistamine and the other one of the first and second dosage unitscomprises a cough suppressant.
 7. The combination of claim 2, wherein atleast the first dosage unit comprises an antihistamine.
 8. Thecombination of claim 2, wherein at least the second dosage unitcomprises a cough suppressant.
 9. The combination of claim 7, wherein atleast the second dosage unit comprises a cough suppressant.
 10. Thecombination of claim 2, wherein the first dosage unit further comprisesat least one active ingredient selected from chlorpheniramine,promethazine, carbetapentane, diphenhydramine, codeine andpharmaceutically acceptable salts thereof.
 11. The combination of claim2, wherein the first dosage unit further comprises at least one ofdiphenhydramine and a pharmaceutically acceptable salt thereof.
 12. Thecombination of claim 2, wherein the second dosage unit further comprisesat least one active ingredient selected from chlorpheniramine,dexchlorpheniramine, diphenhydramine, carbinoxamine, hydrocodone,codeine, guaifenesin and pharmaceutically acceptable salts thereof. 13.The combination of claim 2, wherein the second dosage unit furthercomprises at least one of diphenhydramine and a pharmaceuticallyacceptable salt thereof.
 14. The combination of claim 1, wherein thefirst dosage unit comprises from about 50 mg to about 130 mg ofpseudoephedrine hydrochloride or an equivalent amount of at least one ofpseudoephedrine and any other pharmaceutically acceptable salt thereof.15. The combination of claim 1, wherein the second dosage unit comprisesfrom about 40 mg to about 80 mg of phenylephrine hydrochloride or anequivalent amount of at least one of phenylephrine and any otherpharmaceutically acceptable salt thereof.
 16. The combination of claim1, wherein the first dosage unit comprises from about 60 mg to about 120mg of pseudoephedrine hydrochloride or an equivalent amount of at leastone of pseudoephedrine and any other pharmaceutically acceptable saltthereof and the second dosage unit comprises from about 50 mg to about75 mg of phenylephrine hydrochloride or an equivalent amount of at leastone of phenylephrine and any other pharmaceutically acceptable saltthereof.
 17. The combination of claim 16, wherein the first dosage unitfurther comprises at least one of diphenhydramine and a pharmaceuticallyacceptable salt thereof.
 18. The combination of claim 16, wherein thesecond dosage unit further comprises at least one of diphenhydramine anda pharmaceutically acceptable salt thereof.
 19. The combination of claim16, wherein both the first dosage unit and the second dosage unitfurther comprises at least one of diphenhydramine and a pharmaceuticallyacceptable salt thereof.
 20. The combination of claim 1, wherein thefirst dosage unit and the second dosage unit each independently compriseat least one of a tablet, a capsule, a powder, a solution, a suspension,a gel and a syrup.
 21. The combination of claim 20, wherein the firstand second dosage units each comprise a suspension.
 22. The combinationof claim 20, wherein the first and second dosage units each comprise atablet.
 23. The combination of claim 1, wherein at least the seconddosage unit comprises a controlled release formulation.
 24. Thecombination of claim 1, wherein at least one of the first and seconddosage units comprises a multilayered tablet.
 25. The combination ofclaim 24, wherein the first and second dosage units both comprise amultilayered tablet.
 26. The combination of claim 24, wherein the firstdosage unit comprises a multilayered tablet comprising at least a firstlayer which is an immediate release layer and a second layer which is acontrolled release layer.
 27. The combination of claim 26, wherein thefirst layer of the first dosage unit comprises an antihistamine.
 28. Thecombination of claim 24, wherein the second dosage unit comprises amultilayered tablet comprising at least two different controlled releaselayers.
 29. The combination of claim 28, wherein at least one of thecontrolled release layers comprises a cough suppressant.
 30. Thecombination of claim 1, wherein the combination is a packagedcombination comprising the one or more first dosage units contained inat least one first container and the one or more second dosage unitscontained in at least one second container.
 31. The combination of claim1, wherein the combination further comprises instructions directingingestion of the first dosage units prior to periods during which asubject intends to be awake and ingestion of the second dosage unitsprior to periods during which a subject intends to sleep.
 32. A packagedcombination of oral dosage units for alleviating respiratory ailments,wherein the combination comprises: (a) one or more first dosage unitswhich comprise at least one of pseudoephedrine and a pharmaceuticallyacceptable salt thereof and further comprises an antihistamine; and (b)one or more second dosage units which comprise at least one ofphenylephrine and a pharmaceutically acceptable salt thereof and furthercomprises a cough suppressant; and wherein the first and second dosageunits are different and separate from each other.
 33. The combination ofclaim 32, wherein the antihistamine of the one or more first dosageunits comprises at least one of diphenhydramine and a pharmaceuticallyacceptable salt thereof.
 34. The combination of claim 32, wherein theone or more second dosage units further comprise an antihistamine. 35.The combination of claim 32, wherein the first dosage unit comprisesfrom about 60 mg to about 120 mg of pseudoephedrine hydrochloride or anequivalent amount of at least one of pseudoephedrine and any otherpharmaceutically acceptable salt thereof.
 36. The combination of claim35, wherein the second dosage unit comprises from about 50 mg to about75 mg of phenylephrine hydrochloride or an equivalent amount of at leastone of phenylephrine and any other pharmaceutically acceptable saltthereof.
 37. The combination of claim 32, wherein the first and seconddosage units each comprise a tablet.
 38. The combination of claim 36,wherein the first dosage unit comprises a multilayered tablet.
 39. Thecombination of claim 37, wherein the second dosage unit comprises amultilayered tablet.